Composite co-activator ARC mediates chromatin-directed transcriptional activation

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Abstract
Gene activation in eukaryotes is regulated by complex mechanisms in which the recruitment and assembly of the transcriptional machinery is directed by gene- and cell-type-specific DNA-binding proteins1. When DNA is packaged into chromatin, the regulation of gene activation requires new classes of chromatin-targeting activity2. In humans, a multisubunit cofactor functions in a chromatin-selective manner to potentiate synergistic gene activation by the transcriptional activators SREBP-1a and Sp1 (ref. 3). Here we show that this activator-recruited cofactor (ARC) interacts directly with several different activators, including SREBP-1a, VP16 and the p65 subunit of NF-κB, and strongly enhances transcription directed by these activators in vitro with chromatin-assembled DNA templates. The ARC complex consists of 16 or more subunits; some of these are novel gene products, whereas others are present in other multisubunit cofactors, such as CRSP4, NAT5 and mammalian Mediator6. Detailed analysis indicates that the ARC complex is probably identical to the nuclear hormone-receptor cofactor DRIP7. Thus, ARC/DRIP is a large composite co-activator that belongs to a family of related cofactors and is targeted by different classes of activator to mediate transcriptional stimulation.